Metformin reverses PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 upregulation in triple-negative breast cancer

American Journal of Cancer Research

Chia-Wei Li¹  Ye Han²  Jung-Mao Hsu³ 

[1]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

[2]The Second Breast Surgery Ward, Shengjing Hospital of China Medical University, Shenyang, Peoples Republic of China

[3]Thyroid and Pancreatic Surgery Ward, Shengjing Hospital of China Medical University, Shenyang, Peoples Republic of China

关键词: PARP;    epithelial-mesenchymal transition;    PD-L1;    triple-negative breast cancer;    metformin;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors (PARPi) has been described in some patients lowering the overall response rates. To investigate the underlying mechanisms of PARPi resistance, we developed the adaptive resistant clones in triple-negative breast cancer cell lines. We identified epithelial-mesenchymal transition (EMT) and upregulation of programmed death-ligand 1 (PD-L1) in resistant cells and further demonstrated the important role of Akt S473 phosphorylation in PARPi resistance. In addition, PARPi mediated EMT is independent of PD-L1 upregulation. Blocking the p-Akt S473 axis by metformin reversed EMT and PD-L1 expression which sensitized PARPi-resistant cells to cytotoxic T cells. Thus, a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to immunotherapy.

【 授权许可】

CC BY-NC